Clinical Utility Gene Card

European Journal of Human Genetics (2011) 19, doi:10.1038/ejhg.2010.109; published online 21 July 2010

There is a CUGC Update (January 2013) associated with this article.

Clinical utility gene card for: Lesch–Nyhan syndrome

Rosa J Torres1, Juan G Puig2 and Irène Ceballos-Picot3

  1. 1Biochemistry Laboratory, IdiPAZ- Instituto de Investigación Sanitaria del Hospital Universitario La Paz-Universidad Autónoma de Madrid, La Paz Hospital, Paseo de la Castellana, Madrid, Spain
  2. 2Internal Medicine Department, IdiPAZ- Instituto de Investigación Sanitaria del Hospital Universitario La Paz-Universidad Autónoma de Madrid, La Paz Hospital, Paseo de la Castellana, Madrid, Spain
  3. 3Metabolic Biochemistry Laboratory, Hôpital Necker-Enfants Malades, Paris, France

Correspondence: Dr RJ Torres, Biochemistry Laboratory, Instituto de Investigación Sanitaria del Hospital Universitario La Paz-Universidad Autónoma de Madrid, La Paz Hospital, Paseo de la Castellana 261, Madrid 28046, Spain. Tel: +34 917277343; Fax: +34 91 2071468; E-mail: rtorres.hulp@salud.madrid.org

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1. DISEASE CHARACTERISTICS

1.1 Name of the disease (synonyms)

Hypoxanthine guanine phosphoribosyltransferase (HPRT)-1 deficiency

HPRT1 deficiency

HPRT deficiency

HPRT deficiency, complete

HPRT deficiency, grade IV

1.2 OMIM# of the disease

300322.

1.3 Name of the analyzed genes or DNA/chromosome segments

HPRT1.

1.4 OMIM# of the gene(s)

308000.

1.5 Mutational spectrum

Human HPRT is encoded by a single structural gene spanning approximately 45kb on the long arm of the X chromosome at Xq26, and consists of nine exons with a coding sequence of 654bp. Documented mutations in HPRT deficiency show a high degree of heterogeneity in type and location within the HPRT1 gene: deletions, insertions, duplications, and point mutations have been described as the cause of HPRT deficiency. To date, more than 300 disease-associated mutations have been found.1, 2, 3, 4

1.6 Analytical methods

HPRT1 gene is a housekeeping gene and it is expressed in peripheral blood. Most HPRT-deficient patients, biochemically diagnosed by a null HPRT activity in erythrocytes, present HPRT mRNA expression, and molecular diagnosis can be accomplished by RNA extraction, reverse transcription-PCR, and HPRT complementary DNA (including 3′ and 5′ regions) sequencing. In other cases, genomic DNA sequencing of the nine HPRT1 exons, with its intronic flanquing sequences, may be necessary. In some cases, the HPRT coding region is normal and the patients present a decrease HPRT mRNA expression of unknown origin. In these patients quantification of HPRT mRNA by real-time PCR may be used for molecular diagnosis.5, 6, 7, 8, 9

Inheritance of HPRT deficiency is X-linked recessive. Thus, males are generally affected and heterozygous females are carriers. However, at least five females with Lesch–Nyhan syndrome have been described, with different molecular alterations accounting for their HPRT deficiency.10, 11, 12, 13, 14, 15, 16 Carrier diagnosis is an important issue for most HPRT-deficient families. Female carriers cannot be detected without the help of a laboratory, as they are usually asymptomatic. Carrier status cannot be accurately assessed by biochemical and enzymatic methods. HPRT activity is most often normal in hemolysate of the peripheral blood of female carriers due to selection against HPRT-deficient erythrocyte precursors. Enzymatic diagnosis of the carrier state can be performed by the identification of HPRT-deficient hair follicles or cultured fibroblasts because of their mosaicism in terms of HPRT activity, although such diagnosis is not infallible. HPRT-deficient cells from carrier females can be selected based on their 6-thioguanine resistances. Proliferation assay of peripheral blood T lymphocytes in the presence of 6-thioguanine is diagnostic in most cases. However, faster and more accurate carrier diagnosis can be performed by molecular methods. Carrier diagnosis can be accomplished by genomic DNA sequencing of the HPRT1 gene fragment where the mutation was found in the family propositus. When propositus mutation is not available, amplification of the nine HPRT1 exons, with its intronic flanquing sequences, may be necessary. If a deletion has been found in the propositus, gene dosage may be accomplished by quantitative PCR or multiplex ligation-dependent probe amplification.17, 18

Prenatal diagnosis for Lesch–Nyhan syndrome can be performed with amniotic cells obtained by amniocentesis at about 15–18 week's gestation, or chorionic villus cells obtained at about 10–12 week's gestation. Both HPRT enzymatic assay and molecular analysis for the known disease-causing mutation can be performed.

1.7 Analytical validation

Mutation found in HPRT complementary DNA must be confirmed at genomic level.

1.8 Estimated frequency of the disease

(Incidence at birth (‘birth prevalence’) or population prevalence):

The prevalence of the disease is estimated to be 1/380000 live births in Canada, and 1/235000 live births in Spain.19

1.9 If applicable, prevalence in the ethnic group of investigated person

There is no difference in prevalence for a specific ethnic group.

1.10 Diagnostic setting

Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Comment: When enzymatic diagnosis is not available clinical and molecular diagnosis must be performed.

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2. TEST CHARACTERISTICS

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2.1 Analytical sensitivity (proportion of positive tests if the genotype is present)

About 95% (In a 5% of patients the molecular defect causing HPRT deficiency is not found. These patients present decreased HPRT1 expression of unknown cause.)

2.2 Analytical specificity (proportion of negative tests if the genotype is not present)

100%.

2.3 Clinical sensitivity (proportion of positive tests if the disease is present)

The clinical sensitivity can be dependent on variable factors such as age or family history. In such cases a general statement should be given, even if a quantification can only be performed case by case.

About 95% (In a 5% of patients the molecular defect causing HPRT deficiency is not found. These patients present decreased HPRT1 expression of unknown cause.)

2.4 Clinical specificity (proportion of negative tests if the disease is not present)

The clinical specificity can be dependent on variable factors such as age or family history. In such cases a general statement should be given, even if a quantification can only be performed case by case.

100%.

2.5 Positive clinical predictive value (lifetime risk to develop the disease if the test is positive)

100%.

2.6 Negative clinical predictive value (probability not to develop the disease if the test is negative)

Assume an increased risk based on family history for a non-affected person. Allelic and locus heterogeneity may need to be considered.

Index case in that family had been tested:

100%.

Index case in that family had not been tested:

In some rare cases (5%) standard genetic tests are not informative for diagnosis in spite of the HPRT enzymatic activity is null or decreased. In these cases diagnosis has to be made by enzymatic methods.

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3. CLINICAL UTILITY

3.1 (Differential) diagnosis: the tested person is clinically affected

(To be answered, if in 1.10 ‘A’ was marked)

3.1.1 Can a diagnosis be performed other than through a genetic test?
 

Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

3.1.2 Describe the burden of alternative diagnostic methods to the patient
 

Enzymatic test for HPRT activity in hemolysate or intact cells are of diagnostic and pronostic value.

3.1.3 How is the cost-effectiveness of alternative diagnostic methods to be judged?
 

Enzymatic test are laborious and they are not available in many laboratories (see http://www.lesch-nyhan.org and http://www.orpha.net for the list).

3.1.4 Will disease management be influenced by the result of a genetic test?
 

Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

3.2 Predictive setting: the tested person is clinically unaffected but carries an increased risk based on family history

(To be answered, if in 1.10 ‘B’ was marked)

3.2.1 Will the result of a genetic test influence lifestyle and prevention?
 

If the test result is positive (please describe)

If the test result is negative (please describe)

3.2.2 Which options in view of lifestyle and prevention does a person at-risk have if no genetic test has been performed (please describe)?
 

3.3 Genetic risk assessment in family members of a diseased person

(To be answered, if in 1.10 ‘C’ was marked)

Molecular testing of potential heterozygous carrier in a family.

3.3.1 Does the result of a genetic test resolve the genetic situation in that family?
 

Yes.

3.3.2 Can a genetic test in the index patient save genetic or other tests in family members?
 

No.

3.3.3 Does a positive genetic test result in the index patient enable a predictive test in a family member?
 

Yes.

3.4 Prenatal diagnosis

(To be answered, if in 1.10 ‘D’ was marked)

Prenatal diagnosis possible when the causal mutation identified in the index case and diagnosis of the carrier performed.

3.4.1 Does a positive genetic test result in the index patient enable a prenatal diagnostic?
 

Yes.

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4. IF APPLICABLE, FURTHER CONSEQUENCES OF TESTING

Please assume that the result of a genetic test has no immediate medical consequences. Is there any evidence that a genetic test is nevertheless useful for the patient or his/her relatives? (Please describe).

Molecular diagnosis in the proband allows a more accurate and faster carrier and prenatal diagnosis in relatives.

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Conflict of interest

The authors declare no conflict of interest.

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References

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Acknowledgements

This work was supported by EuroGentest, an EU-FP6 supported NoE, contract number 512148 (EuroGentest Unit 3: ‘Clinical genetics, community genetics and public health’, Workpackage 3.2).